Parkinson's disease is a common human neurodegenerative movement disorder and affects 1% of the elderly population (see discussion by Kapurniotu (2004) Chemistry & Biology 11, pp 1476-1478). Primary clinical symptoms of PD are bradykinesia, resting tremor, muscular rigidity, and difficulty with balance. PD is neuropathologically characterized by a marked and progressive degeneration of dopaminergic neurons and by the presence of fibrillar cytoplasmic inclusions (Lewy bodies [LBs]) and dystrophic neurites (Lewy neurites [LNs]) in the substantia nigra and other regions of the brain (Recchia et al. (2004) FASEB J 18: 617-626).
Although the loss of dopamine neurons is certainly related to the major clinical symptoms of PD, the causes and the pathogenesis of this multifactorial disease as well as that of related “synucleinopathies” are still largely unknown.
The major components of both LBs and LNs are fibrillar aggregates of α-synuclein. α-Synuclein is a widely expressed, neuronal presynaptic protein that appears to play a role in membrane-associated processes and synaptic plasticity and has been linked to learning and development processes. While the mechanism(s) of formation of LBs and LNs and their association with PD are yet not understood, several lines of evidence suggest that α-synuclein fibrillization is associated with PD and that α-synuclein fibrillization causes toxicity (see e.g. Masliah et al., Science, 287:1265-1269 (2000); Feany et al., Nature 404:394-8 (2000)).
In addition to α-synuclein, β-synuclein has also been implicated in neurodegenerative synucleinopathies. Human β-synuclein is a 134-residue neuronal protein that is 78% homologous to α-synuclein. The α- and β-synucleins share a conserved C-terminus with three identically placed tyrosine residues. In addition to α-synuclein-containing LBs and LNs, the development of PD and dementia with LBs is accompanied by the appearance of novel α- and β-synuclein-positive lesions in hippocampus (Galvin et al. 1999) implicating β-synuclein, in addition to α-synuclein, in the onset and progression of these diseases. It has been indicated that β-synuclein may regulate α-synuclein fibrillation, perhaps acting as a chaperone to minimize the aggregation of α-synuclein (Hashimoto et al. 2001; Uversky et al. 2002; Park and Lansbury, 2002). Thus a decrease in the levels of β-synuclein has been considered as a possible factor in the PD etiology (Uversky et al. 2002).
Thus the inhibition or reversal of synuclein aggregation is believed to be of therapeutic benefit.
Li et al. (2004) Chemistry & Biology 11: pp 1513-1521 discuss the inhibition of α-synuclein fibrillization, and the disaggregation of fibrils, by the antibiotic rifampicin.
Zhu et al. (2004) Journal of Biological Chemistry 279, 26: pp 26846-26857 discuss the inhibition of α-synuclein fibrillization, and the disaggregation of fibrils, by the flavanoid baicalein.
There are a number of other publications in the art said to be concerned with the inhibitors of such aggregation. These include “Compositions for inhibiting the aggregation pathway of alpha-synuclein” (U.S. Pat. No. 6,780,971-2004-08-24); “Polyhydroxylated aromatic compounds for the treatment of amyloidosis and alpha-synuclein fibril diseases” (US2004152760-2004-08-05); Peptide and peptide derivatives for the treatment of alpha-synuclein related diseases (WO2004009625-2004-01-29); Proanthocyanidins for the treatment of amyloid and alpha-synuclein diseases (EP1377287-2004-01-07); Methods for preventing neural tissue damage and for the treatment of alpha-synuclein diseases (CN1440420T-2003-09-03).
However, it will be understood that the provision of compounds not previously known to be capable of inhibiting synuclein aggregation would provide a contribution to the art.